This invention relates to a pharmaceutical composition comprising a tricyclic compound of general formula (I) or a pharmaceutically acceptable salt thereof which features stability, excellent absorbability, and/or a reduced irritation potential. This pharmaceutical composition is of value for the treatment or prevention of inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases.
The tricyclic compound (I) and its pharmaceutically acceptable salt for use in accordance with this invention is known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs.-host diseases, autoimmune diseases, and infectious diseases [Japanese Kokai Tokkyo Koho S61-1481B1, EP-A-0323042, etc.].
Particularly, those species of tricyclic compound (I) which are designated as FR900506 (=FK506 Substance), FR900520, FR900523, and FR900525 are products produced by microorganisms of the genus Streptomyces, such as Streptomyces tsukubaensis No. 9993 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit Oct. 5, 1984, accession number FERM BP-927] or Streptomyces hygroscopicus subsp. vakushimaensis No. 7238 [deposited with National Institute off Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit Jan. 12, 1985, accession number FERM BP-928]. The FK506 Substance of the following chemical formula, in particular, is a representative compound. 
Chemical name: 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9] octacos-18-ene-2,3,10, 16-tetraone
It has been demonstrated that the above-mentioned FK506 Substance has quite excellent immunosuppressive activity and is useful for the treatment or prevention of rejection by organ transplantation and the treatment or prevention of diseases in the field of ophthalmology.
Japanese Kokai Tokkyo Koho H1-157913 discloses that a solution of FK506 Substance in ethanol is effective in the suppression of inflammation and that FK506 Substance can be formulated into a lotion, gel, or cream. However no specific dosage forms of the kinds are described.
Japanese Kokai Tokkyo Koho H5-17481 discloses an ointment comprising a tricyclic compound (I) or its pharmaceutically acceptable salt, at least a sufficient amount of a dissolution/absorption promoter to dissolve the same, and an ointment base.
W094/28894 discloses a lotion comprising a tricyclic compound (I) or its pharmaceutically acceptable salt, a dissolution/absorption promoter, a liquid medium, and optionally an emulsifier and/or a thickening (rheology modifier).
Heretofore, ointments have mainly been used in the treatment of skin diseases. However, different dosage forms suited to different clinical manifestations and different application sites are being demanded.
The inventors of this invention have studied possible pharmaceutical compositions for compounds of general formula (I) inclusive of FK506 Substance and found a dosage form having many desirable characteristics such as high stability, high transdermal absorbability, and/or reduced dermal irritancy. Thus, specifically this invention is directed to an hydrophilic semi-solid composition for external use containing said tricyclic compound.
In accordance with this invention there is provided a pharmaceutical composition comprising a tricyclic compound (I) or its pharmaceutically acceptable salt, an oil substance, a surfactant, a hydrophilic substance, and water, and further optionally a pH control agent.
The tricyclic compound for use in this invention can be expressed by the following general formula (I). 
(wherein each of adjacent pairs of R1 and R2, R3 and R4 or R5 and R6 independently
(a) is two adjacent hydrogen atoms, or
(b) may form another bond formed between the carbon atoms to which they are attached, and further, R2 may be an alkyl group;
R7 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group, or an oxo group together with R1;
each of R8 and R9 is independently a hydrogen atom or a hydroxy group;
R10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group;
X is an oxo group, (a hydrogen atom and a hydroxy group) (a hydrogen atom and a hydrogen atom), or a group represented by the formula xe2x80x94CH2Oxe2x80x94;
Y is an oxo group, (a hydrogen atom and a hydroxy group) (a hydrogen atom and a hydrogen atom), or a group represented by the formula Nxe2x80x94NR11R12 or Nxe2x80x94OR13; 
each of R11 and R12 is independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
each of R13, R14, R15, R16, R17, R18, R19, R22 and R23 is independently a hydrogen atom or an alkyl group;
each of R20 and R21 is independently an oxo group or (R20a and a hydrogen atom) or (R21a and a hydrogen atom) in which each of R20a and R21a is independently a hydroxy group, an alkoxy group or a group represented by the formula xe2x80x94OCH2OCH2CH2OCH3, or R21a is a protected hydroxy group, or R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is an integer of 1 or 2; and
in addition to the above definitions, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkyl substituted by one or more hydroxy groups, an alkoxy, a benzyl and a group of the formula xe2x80x94CH2Se (C6H5)).
The above compound (I) or its pharmaceutically acceptable salt can be provided by the same technology as that described in the two patent gazettes referred to above. Particularly, the tricyclic compounds produced by fermenting Streptomyces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces hygroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928) are known by the identification nos. of FR-900506, FR-900520, FR-900523, and FR-900525 (Japanese Kokai Tokkyo Koho S61-148181).
The various definitions given in the above general formula (I), generic and subgeneric examples thereof, and preferred species are now explained and shown in detail.
The term xe2x80x9clowerxe2x80x9d means, unless otherwise indicated, a group having 1 to 6 carbon atoms.
Preferable examples of the xe2x80x9calkyl groupsxe2x80x9d include a straight or branched chain aliphatic hydrocarbon residue for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl.
Preferable examples of the xe2x80x9calkenyl groupsxe2x80x9d include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
Preferable examples of the xe2x80x9caryl groupsxe2x80x9d include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl.
Preferable protective groups in the xe2x80x9cprotected hydroxy groupsxe2x80x9d are 1-(lower alkylthio) (lower) alkyl group such as a lower alkylthiomethyl group (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more preferably C1-C4 alkylthiomethyl group, most preferably methylthiomethyl group;
trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyl-diarylsilyl (e.g., methyldiphenylsilyl, ethyldimethylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl, etc.), more preferably tri(C1xe2x80x94C4)alkylsilyl group and C1-C4 alkyldiphenylsilyl group, most preferably tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
Examples of the aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, arboxyhexanoyl, etc.; a cyclo(lower)alkoxy(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy(lower)alkylcarbamoyl group (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), tri-lower)alkylsilyl(lower)alkoxycarbonyl(lower)-alkylcarbamoyl group (e.g., trimethylsilylmethoxy-carbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, tri-methylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
Examples of the aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
Examples of the aliphatic acyl groups substituted by an aromatic group include ar(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo(lower)alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc.
More preferable acyl groups among the aforesaid acyl groups are C1-C4 alkanoyl group optionally having carboxy, cyclo(C5-C6)alkoxy(C1-C4)alkanoyl group having two (C1-C4) alkyls at the cycloalkyl moiety, camphorsulfonyl group, carboxy(C1-C4)alkylcarbamoyl group, tri(C1-C4)alkylsilyl(C1-C4)alkoxycarbonyl(C1-C4)alkylcarbamoyl group, benzoyl group optionally having one or two nitro groups, benzenesulfonyl group having halogen, orphenyl(C1-C4)alkanoyl group having C1-C4 alkoxy and trihalo(C1-C4)alkyl group. Among these, the most preferable ones are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.
Preferable examples of the xe2x80x9c5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ringxe2x80x9d include a pyrrolyl group and a tetrahydrofuryl group.
The pharmaceutically acceptable salt of the compound (I) includes conventional non-toxic and pharmaceutically acceptable salt such as the salt with inorganic or organic bases, specifically, an alkali metal salt such as sodium salt and potassium salt, an alkali earth metal salt such as calcium salt and magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.
With respect to the compound (I), it is to be understood that there may be conformers and one or more stereoisomers such as optical and geometrical isomers due to asymmetric carbon atom(s) or double bond(s), and such conformers and isomers are also included within the scope of the present invention.
The compound of the formula (I) or its pharmaceutically acceptable salt can be in the form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
The preferred examples of the tricyclic compound (I) is the one, wherein each of adjacent pairs of R3 and R4 or R5 and R6 independently form another bond formed between the carbon atoms to which they are attached;
each of R8 and R23 is independently a hydrogen atom;
R9 is a hydroxy group;
R10 is a methyl group, an ethyl group, a propyl group or an allyl group;
X is (a hydrogen atom and a hydrogen atom) or an oxo group;
Y is an oxo group;
each of R14, R15, R16, R17, R18, R19, and R22 is a methyl group;
each of R20 and R21 is independently (R20a and a hydrogen atom) or (R21a and a hydrogen atom) in which each of R20a and R21a is a hydroxy group or an alkoxy group, or R21a is a protected hydroxy group; and
n is an integer of 1 or 2.
FK506 Substance is the most preferable compound belonging to the tricyclic compound (I). Other preferable compounds are listed hereinbelow.
1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,17,19,21,27-pentamethyl-11,28-dioxa-4-azatricyclo[(22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-12-[2-[4-(3,5-dinitrobenzoyloxy)-3-methoxycyclo-hexyl]-1-methylvinyl]-11,28-dioxa-4-azatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone,
17-allyl-12-[2-[4-[(xe2x88x92)-2-trifluoromethyl-2-methoxy-2-phenylacetoxy]-3-methoxycyclohexyl]-1-methylvinyl]-1, 14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone.
17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FR900520), and
17-ethyl-1,14,20-trihydroxy-12-[2-(3,4-dihydroxycyclo-hexyl)-1-methylvinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo(22.3.1.04,9]octacos-18-ene-2,3,10,16-etraone.
The oil substance for use in this invention need only to be a substance capable of dissolving tricyclic compound (I) or its pharmaceutically acceptable salt. Preferable ones are, for example, fatty acid esters and alcohols.
Monohydric alcohol fatty acid esters (isopropyl myristate, ethyl myristate, butyl myristate, isocetyl myristate, octyldodecyl myristate, isopropyl palmitate, isostearyl palmitate, isopropyl isostearate, isocetyl isostearate, butyl stearate, isocetyl stearate, cetyl isooctanoate, ethyl linoleate, isopropyl linoleate, hexyl laurate, ethyl oleate, decyl oleate, oleyl oleate, octyl dodecyl myristate, hexyl decyl dimethyloctanoate, octyl dodecyl neodecanoate, etc.)
Dibasic acid diesters (diisopropyl adipate, dimethyl adipate, diethyl adipate, diisobutyl adipate, diethyl sebacate, diisopropyl sebacate, dipropyl sebacate, diethyl phthalate, diethyl pimelate, etc.)
Alcohols (oleyl alcohol, cetanol, stearyl alcohol, 2-octyldodecanol, etc.)
In this invention the above-mentioned oil substances can be used independently or in a combination of two or more species.
Particularly from the standpoint of stability of the dosage form, absorbability and/or irritation potential, it is preferable, in many instances, to use a plurality of such oil substances in combination. The preferred combination may for example be a mixture of a monohydric alcohol fatty acid ester (e.g. isopropyl myristate) and a dibasic acid diester (e.g. diethyl sebacate) in a suitable weight ratio (e.g. 0.1xcx9c10:1 (w/w), preferably 0.5xcx9c2:1 (w/w)) . The most preferable weight ratio thereof is 1:1 (w/w).
The proportion of the oil substance in the pharmaceutical composition is preferably 2xcx9c50% (w/w), more preferably 10xcx9c40%, and most preferably 20xcx9c30%.
The surfactant for use in this invention is now described.
The surfactant that can be used includes pharmaceutically acceptable ionic or nonionic surfactants but is preferably a nonionic surfactant with an HLB number of not less than 10. More preferably, the following ether series and ester series surfactants can be mentioned.
Ethers
Polyoxyethylene alkyl ethers (polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether (Lauromacrogol J.P.), polyoxyethylene behenyl ether, etc.)
Esters
Polyoxyethylene sorbitan fatty acid esters Polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, etc. (e.g. Tween 20, Tween 40, Tween 60, Tween 65, Tween 80, etc., all trademarks)
Polyethylene glycol fatty acid esters (polyethylene glycol monooleate, polyethylene glycol monostearate (e.g. polyoxyl stearate 40 J.P.), polyethylene glycol monolaurate, etc.)
Pentaglycerol fatty acid esters Pentaglycerol monolaurate, pentaglycerol monomyristate, pentaglycerol monooleate, pentaglycerol monostearate, etc.
Glycerol fatty acid esters Glyceryl monostearate etc.
In working this invention, the above-mentioned surfactants can be used independently or in a combination of two or more species. The proportion of the surfactant in the pharmaceutical composition is preferably 0.1xcx9c15% (w/w) and more preferably 0.5xcx9c5%(w/w).
The hydrophilic substance for use in this invention may be any substance that is pharmaceutically acceptable and capable of imparting viscosity to liquids, thus including the following organic or inorganic hydrophilic substances.
(1) Organic Substances
{circle around (1)} Natural polymers . . . gum arabic, guar gum, carrageenin, gum tragacanth, pectin, starch, gum xanthan, gelatin, casein, dextrin, cellulose
{circle around (2)} Semi-synthetic polymers . . . methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxy-propylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylstarch, sodium alginate, propylene glycol alginate,
{circle around (3)} Synthetic polymers . . . carboxyvinyl polymer (Carbopol) polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyvinyl methyl ether, sodium polyacrylate
(2) Inorganic substances Bentonite, synthetic magnesium silicate, magnesium aluminosilicate, silicon oxide, etc.
The proportion of the hydrophilic substance in the pharmaceutical composition of this invention is selected according to the desired viscosity of the pharmaceutical composition and is preferably 0.1xcx9c10% (wlw) and more-preferably 0.5xcx9c2%.
Furthermore, in the instant invention, the pharmaceutical composition is preferably maintained at a constant pH from safety points of view. Therefore, a pH control agent such as a buffer, an aqueous solution of sodium hydroxide, or the like can be added in a suitable amount. The pH range is preferably 3.5xcx9c6 and more preferably 4xcx9c5.
Where necessary, in addition to the above ingredients, the conventional excipient (e.g. petrolatum, propylene glycol, etc.), stabilizer (antioxidant etc.), coloring agent, sweetener, flavor, diluent, antiseptic (e.g. parahydroxybenzoates, benzalkonium chloride, sorbic acid, etc.), and other drug substances effective against diseases of the skin can be added.
Meanwhile, the pharmaceutical composition of this invention can be produced by a process comprising the following steps.
(1) A step which comprises preparing a solution composed of said tricyclic compound (I) or pharmaceutically acceptable salt thereof, oil substance, and surfactant;
(2) a step which comprises mixing the solution with water to give an emulsion; and
(3) a step which comprises mixing the emulsion with said hydrophilic substance, and further optionally pH control agent, with stirring. As an alternative, this step may comprise mixing said hydrophilic substance, and further optionally pH control agent, with water and, then, mixing the premix with the emulsion prepared as above with stirring.
The step (1) is preferably carried out at elevated temperature, for example at 50xcx9c90xc2x0 C., preferably 60xcx9c80 xc2x0 C.
In step (2), the water for use is also preferably heated ahead of time to a temperature close to that of the solution prepared in step (1), and the resulting emulsion is preferably cooled to a suitable temperature, for example 30xc2x0 C., before step (3) is carried out.
The dosage of tricyclic compound (I) or its pharmaceutically acceptable salt depends on the individual patient""s age and the type and severity of disease but the usual daily therapeutic dose is about 0.001xcx9c1000 mg, preferably about 0.005xcx9c500 mg, and more preferably about 0.01xcx9c100 mg, as the active ingredient. Generally, an average of about 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, or 50 mg per dose is administered.
The recommended proportion of tricyclic compound (I) in the pharmaceutical composition is 0.001xcx9c20% (w/w) preferably 0.01xcx9c10% (w/w), of the total composition.